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. 2012 Nov 12;109(48):19846–19851. doi: 10.1073/pnas.1211517109

Fig. 5.

Fig. 5.

(A) Relationship between KNDy neurons, GnRH neurons, and the heat-defense pathway in the rat. KNDy neurons branch within the arcuate nucleus and project to GnRH terminals in the median eminence (22, 56) and preoptic areas that regulate body temperature, including the MnPO (22–24, 42, 45, 48). Secretion of GnRH into portal capillaries stimulates LH secretion from the anterior pituitary gland, which stimulates the secretion of E2 from the ovaries. E2 negative feedback reduces serum LH and decreases NKB and kisspeptin mRNA in KNDy neurons (57, 58). ERα, the isoform required for estrogen negative feedback (59), is expressed in arcuate KNDy neurons (60) but not GnRH neurons (61). NK3R is expressed on arcuate KNDy neurons (60) and GnRH terminals in the median eminence (56). GnRH neurons express kisspeptin receptor mRNA (62), but the distribution of the kisspeptin receptor protein on GnRH neurons has not been described. MnPO neurons express NK3R and pharmacological activation of these neurons reduces body temperature (25). The MnPO receives information from warm-sensitive, cutaneous thermoreceptors and projects to CNS centers to modulate heat-dissipation effectors (24, 42). (B) Effects of ovariectomy on serum LH and tail skin vasodilatation: Loss of E2 after ovariectomy markedly increases NKB and kisspeptin gene expression in KNDy neurons (57, 58), increases GnRH secretion into the portal capillaries (63) and LH secretion from the anterior pituitary gland. In the MnPO, at neutral TAMBIENT, Fos is increased in OVX rats, compared with OVX + E2 rats (37). Tail skin vasodilatation is increased by ovariectomy and decreased in OVX rats by E2 replacement (28–31). (C) Effects of KNDy neuron ablation in OVX rats: KNDy neuron ablation lowers serum LH and prevents the rise in LH secretion after ovariectomy (11). Because KNDy neurons do not project to the portal capillary system to directly influence pituitary gonadotrophs (56), this effect is likely mediated via lower levels of GnRH secretion. Ablation of KNDy neurons (with loss of their projections to the rostral hypothalamus) also reduces tail skin vasodilatation. These findings suggest that withdrawal of E2 in OVX rats increases LH secretion and tail skin vasodilatation by increasing the activity of KNDy neurons. AP, anterior pituitary gland; ERα, estrogen receptor α; E2, estradiol-17β; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; Kiss, kisspeptin; KNDy, kisspeptin, neurokinin B, and dynorphin-expressing neurons; MnPO, median preoptic nucleus; NKB, neurokinin B; NK3R, neurokinin 3 receptors; oc, optic chiasm.